Despite the common finding of eosinophils in the gastrointestinal (Gl) tracts of patients suffering from an emerging set of diseases, most studies on eosinophils in vivo have concentrated on trafficking and activation of these cells in the lung. Over the last thirteen years (during the three funding cycles for this grant), we have concentrated our efforts on analyzing the regulation and role of Gl eosinophils at baseline and in allergic inflammatory states. Several fundamental principles have emerged from our studies. In the first grant cycle, we demonstrated that eotaxin-1 provides an essential signal for regulating the baseline and allergen-induced homing of eosinophils into the Gl tract. Furthermore, we established a mechanistic link between the development of eosinophil-associated inflammation in the respiratory tract and the esophagus following specific aeroallergen or cytokine delivery to the lung. We identified a key role for IL-5 in eliciting esophageal eosinophilia and this provided the impetus for clinical trials that tested the role of humanized anti-IL-5 for the treatment of eosinophilic esophagitis (EoE). In the second cycle of this grant, we identified key'roles for Th2 cell adaptive immunity and IL-13 in the pathogenesis of EoE, and proved an eotaxin- receptor dependent mechanism is involved in disease pathogenesis. This provided the rationale for - examining anti-IL-13 in EoE, which is currently ongoing in patients. Furthermore, we focused on mechanisms of esophageal remodeling, identifying a key role for local IL-5-driven eosinophils. In addition, we established a link between T cells, Gl eosinophils and the pro-inflammatory mediator resistin like molecule (Relm)-alpha. Finally, we identified a key role for paired Ig receptor (PIR)-B in negatively regulating Gl eosinophil trafficking. In the third cycle ofthis grant, we demonstrated that Relm-alpha was involved in regulating metabolic responses, orchestrated intestinal inflammation but was dispensable for esophageal and intestinal eosinophilia, although it is a main marker for Gl eosinophils as demonstrated by- whole genome analysis of purified Gl eosinoijhils. IL-13 was demonstrated to be upstream by RELM-alpha induction, and IL-13Ralpha1 and IL-13Ralpha2 were shown to be positive and negative regulators of